3beta-acyloxy-17beta-hydroxy-17alpha-ethynyl-5-androstenes and androstanes and theirpreparation



3,8-ACYLOXY 17/3 HYDROXY 17oz ETHYNYL-S- ANDROSTENES AND ANDRUSTANES AND THEIR PREPARATION Raymond 0. Clinton, North Greenbush Township, and Arthur L. Beyler, Albany, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application July 21, 1955 Serial No. 523,626

17 Claims. (Cl. 260-3975) This invention relates to new 3 9-acyloxy-l7 3-hydroxy- 17a-ethynylandrostanes and 3fi-acyloxy-l7p-hy'droxy-17b:- ethynyl-S-androstenes which have pituitary inhibitory activity without proportionate concomitant estrongenicity or androgenicity.

Of the several hormones secreted by the pituitary gland two produce certain structural and secretory changes in the gonads. These two gonadotropins are the follicilestimulating hormone (FSH) and the interstitial cellstimulating hormone (ICSH). stimulates the testes to develop sex cells, while the ICSH brings about production of the testicular hormone. In the female FSH brings about the growth of the Graafian follicile while the ICSH stimulates ovulation, development of corpus luteum and the production of progesterone. Thus any agent which interferes with the pituitary secretion of FSH and ICSl-I will per force affect the development and endocrine function of the testes and ovaries. Such an agent is useful in the treatment of endocrinological disturbances such as menopausal syndrome, endometriosis, postpartum breast engorgement, benign prostatic hypertrophy, functional uterine bleeding, chronic cystic mastitis, supression or termination of reproductive processes.

The steroidal hormones, estradiol and testosterone, are pituitary inhibitors but their use leads to veryundesirable effects such as feminization and masculinization respectively and in other ways creating a sexual imbalance. Thus, for these steroidal hormones, the ratio of the pituitary inhibition (anti-FSH and anti-ICSH) tothe estrogenic or androgenic activity is low due to the fact that the pituitary elaboration of onadotropin is inhibited but the sex accessory organs are stimulated.

Our new compounds are much more specific than the steroidal hormones as pituitary inhibitors because of their low estrogenic and androgenic activity. The estrogenic activity of our new compounds varies from to $3 that of estradiol and the androgenic activity is of such a low order that it can not be measured unless doses, much too high to have physiological significance, are used. Therefore, the ratio of the anti-FSH or anti- ICSH activity to the estrogenic and androgenic activity In the male the FSH.

. atoms.

is high and hence the compounds have a much higher 'administered orally as 25 mg. capsules'or tablets. The

compounds are active at a level of 0.2-5 nag/kg. body Weight.

ass, Patented Jan. 13, 195p ice ' 2 p v Thecompounds of the invention are new mono esters of 17a-ethynylandrostane-3fl,l7p-diol having the formula w CH3 I 1 050B on and of 17a-ethyny1-5-androstene-3B,17 3-di01 having the formula radicals having from 3 to about 10 carbon atoms and carboxy-alkanoyl radicals having from 4 to 6 carbon The invention also relates to a method for preparation of these new compounds.

In the above general formulas, R can be alkanoyl such as propionyl, butyrl, isobutyryl, valeryl, isovaleryl, tri-v methylacetyl, caproyl, isocaproyl, heptanoyl, octanoyl, nonanoyl, decanoyl, etc., wherein the alkanoyl group has from '3 to about 10 carbon atoms; and carboxy alkanoyl, such as succinyl, glutaryl and adipyl.

Our new compounds are prepared from the known 170tethynylandrostane3;8,l7fl-diol and l7tz-ethynyl-5-androstone-3,8,17,8-diol by esterification with an acylating agent substituent, is sterically hindered and hence less reactive than the unhindered 3-hydroxyl group. Under the above mentioned conditions, the formation of the corresponding diester is sufficiently suppressed to allow isolation of pure mono ester in good yields. readily separated by fractional crystallization or chromatographic separation on silica gel- Although solutions of the mono esters containing some of the corresponding diester can be used, it is preferable to use the pure com pounds in therapy.

The preferred method for preparation of the new compounds is' esterification of the appropriate diol with an acid anhydride at room temperature under anhydrous conditions. The reaction mixture is quenched in dilute acid and the desired product removed by filtration. After recrystallization the pure mono esters are obtained in -90% yields.

Alternatively, the reaction mixture resulting from the esterific'a'tion with either an acid anhydride or acid'halide after quenching in dilute acid can be purified by passage through a chromatographic column.

bility in the ether-n-pentane eluate. The desired mono ester is then obtained by evaporation of the later eluates.

Any diester formedis Any diester formed is removed from the column first due to its greater solu-- The application of heat leadsto the formation of byproducts which necessitate the use of a chromatographic column for satisfactory separation except in the preparation of the carboxyl-acyl compounds which require heating for monoesterification as illustrated in Example 8.

Diesters of 17a-ethynylandrostane-3B,175-diol and 170cethynyl-5 andros'tene-3B',17B-diol can. be prepared by carrying out the above-mentioned procedures at ahigher temperature or for longer periods of time. However, good yields of dies'ter can be obtained by the use of a catalyst such as p toluenesulfonic acid at room temperature as is illustrated inExample 13.

The following examples will further illustrate the invention without limiting the invention thereto.

Example 1 3fi-propionoxy-17B-hydr'oxy --17 a efhynyl 5 androstene.-A solution of 25.16 g. of l7a-ethynyl-5-androstene-3B.17B diol in -150 ml. ,of pure anhydrous pyridine at 25-30 C. was treated with 15.6 g. of pure propionic anhydride. After mixing well, the clear solution while protected from moisturewas kept at 25-30" C. for twenty-four to thirty-six hours. The resulting clear solution was poured into a mixture of 1 kg. of ice, 70 ml. of concentrated sulfuric acid, and 500 ml. of water. The solid which separated was collected by filtration, washed thoroughly with water, and recrystallized first from 50% aqueous methanol, then from 300 ml. of methanol. There was thus obtained 24.98 g. of 3i3-propinoxy-17B- hydroxy-17ot-ethynyl-5-androstene, M. P. 151.4153.2 C. (corn); [a] =-109.9 i0.3 (1% in chloroform).

Analysis.Calcd. for C I-1 C, 77.80; H, 9.25. Found: C, 77.61; H, 9.41.

Example 2 3B-butyroxy-l7fi -hydroxy 1 7a ethynylandrostane was prepared from 3.16 g. of 17a-ethynylandrostane-3B,17/3- diol and 3.0 "ml. of butyric anhydridein 25 ml. of pyridine by the manipulative procedure described .in Example 1. The 1.69 g. of 3fi-but'yr'o'xy 17B hydroxy-1-7a-ethynylandrostane thus obtained had the M. P. 149.8154.6 C. (corn); M13 :-36.1i0.37(1% in chloroform).

Anhlys is.-Calcd. C25H3803I H; 9.91. Found: C, 77.68; H, 10.10.

Example 3 3B-cavr0xy-I7p-hydr0xy 17oz ethynylr'zndrostane was prepared 632 g. of 17a-ethyiiylandrostane-3 3,17B-diol. and 1115 ml. of'caproic anhydride in 50 m1. of pyridineaccording to the manipulative procedure" described in Example 1. The 3.63 g. of 3,8-c'aproxy-17B-hydr0xy-17aethynylandrostane thus obtainedhad tlie'M..P. 118.6- 121.6 C.; [a] =34.3i0.4 (1% in chloroform)- Analysis.-Calcd. for C H O C, 78.21; H, 10.21- Found: C, 78.39; H,,10.50.

Example 5 .diol' and 4.65, g. of N-valeric anhydride in 2 5 ml. of

pure dry pyridine was kept at 25 -35: C. for twenty-four hours under anhydrous conditions. The clear; colorless solution was poured into a mixture of. 500 g. of ice, ml. of concentrated sulfuric acid and 200 ml. of water,

1 and the resulting suspension mixed well and *filtered. The crude product was washed thoroughly with water, dried at 50 C., then dissolved in 50 ml. of pure anhydrous ether and the solution diluted to 400 ml. with npentane. The resultant solution was chromatographed on 200 g. of silica gel using 400 ml. portions, or 12 /270 ether-n-pentane as eluate. The crystalline residues obtained by evaporation of 'the'eighth through the fifteenth fractions were combined and recrytallized three times from n-hexane. There was thus obtained 2.83 g. of 3pvaleroxy-17/3-hydroxy-17a-ethynyl-5-androstene having the M. P. 129.0-131.2 C. (corn); [a] =98.8i0;3 (1% in chloroform). V

Analysis.Calcd. for C H O C, 78.35; H, 9.61. Found: C, 78.27; H, 9.72.

Example 6 .i'fi-butyroxy-I 7 3-lzydro xy-l 7 cz-ethynyl-i-androstene was prepared from 3.14 g. of 17oc-ethynyl-5-androstene-3p, 17fl-diol and 2.4 ml. of butyric anhydride in 25 ml. of pyridine by the manipulative procedure described in Example 5. The 3fl-butyroxy-i7fl-hydroxy-17u ethynyl-5- androstene thus obtained weight 1.37 g. and had the M. -P. ll5.4117.0 C.(corr.); [a] =-l02.5i0.3

(1% in chloroform). 1

Analysis.Calcd. for C H O C, 73.03; H, 9.44.

Found: c, 78.14; H, 9.58.

Example 7 Example 8 3,8-succiu0xy-17,8-hydroxy-1 7ok 'ethynyl-5-dndr0sten'e. A mixture of 3.14 g. of 17u-ethynyl 5-androstene-3B,17,8- diol, 1.50 g. of succinic anhydride and 25 ml. of pure dry pyridine was refluxed under anhydrous conditions for three hours, then poured into a mixture of 300 g. of ice, 10 ml. of concentrated sulfuric acid and 100 ml. of water. The crude product which separated was removed by filtration, washed thoroughly with water and dried at C. The dried material was recrystallized three times from small volumes of methanol to give 1.6 g. of 3/3-succinoxy-17 8-hydroxy 17a-ethynyl-S-androstene, M. P. 203.0204.4 C. (c0rr.); [b] =-92.6i0.7 (0.5% in chloroform).

Analysis.,Calcd. for C H O Found: C, 72.20; H, 8.32.

Example 9 3/3 trimethylacetoxy-I7,8-hydr0xy-Z7ot-ethynylzmdrostane.A mixture of 3.0 g. of trimethylacetic acid, 3.0 g. ofpure thionyl chloride and 10 ml. of pure dry benzene was refluxed under anhydrous conditions for three and one-half hours. The resulting solution was cooled to room temperature (ZS-32 C.) and then a solution of 3.16 g. of 17a-ethynylandrostane-3B,17B-diol in ml. of pure dry pyridine was added. The resulting mixture was allowed to stand at room temperature for seventeen hours. The heterogeneous mixture which resulted was poured into m1. of water and the precipitated semi-solid material extracted into ether. The ethereal solution was washed with dilute hydrochloric acid and then with dilute sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solution was concentrated to a volume of 100 ml., then diluted with 400 ml. of n-pentane and chromatographed on a column of 300 g. silica gel.

The column was eluted with successive 500 ml. portions of a mixture containing 20% ether-80% n-pentane. The combined crystalline material from the evaporation of fractions six through eleven was recrystallized twice from n-hexane to yield 2.14 g. of 3/3-trimethylacetoxy-l7 3-hydroxy-17a-ethynylandrostane, M. P. 2162-2180 C. (corr.); [a] =37.9i0.3 (1% in chloroform).

Analysis.Calcd. for C H O C, 77.95; H, 10.07. Found: C, 78.09; H, 10.19.

Example Example 11 3/3 oetanoyloxy-I 7p-hydr0xy-1 7 a-ethynyl-S -androstene was prepared from 4.71 g. of 17a-ethynyl-5-androstene- 313,17/3-di0l and 2.68 g. of octanoyl chloride in 20 m1. of pyridine according to the method described in Example 9. The 3.12 g. of 3,8-octanoyloxy-17Bhydroxy-l7aethynyl-S-androstene thus obtained had the M. P. 94.0 95.6 C. (corr.); [a] =-87.4i0.4 (1% in chloroform).

Analysis.Calcd. for C H O C, 79.04; H, 10.06. Found: C, 79.22; H, 10.30.

Example 12 3B propionoxy-I 7B-hydr0xy-1 7u-ethynylaizdrostane.-

A mixture of 3.00 g. of 17a-cthynylandrostane-3B,17B- diol, 15 ml. of propionic anhydride and 10 ml. of pure, anhydrous pyridine was heated on the steam bath under anhydrous conditions for forty-five minutes, then poured into 700 ml. of cold water and the heterogeneous mixture allowed to stand for two hours. The precipitate was removed by filtration, washed thoroughly with water, and dried at 70 C. The crude material was dissolved in 80 ml. of pure, dry ether and diluted with 720 ml. of npentane, then chromatographed on a column of 250 g. silica gel. The column was first eluted with nine 800 ml. portions of 10% ether-n-pentane mixture, and then with ten 800 m1. portions of ether-n-pentane mixture. The third, fourth and fifth 20% ether-n-pentane eluates were evaporated to dryness and the resulting crystalline material was recrystallized from methanol to give 1.78 g. of 3B propionoxy-l7,8-hydroxy-17a-ethynylandrostane, M. P. 174.7-177.2 C. (corr.); [a] =-43.3i0.3 (1% in chloroform).

Analysis.-Calcd. for C H O C, 77.37; H, 9.74.

Found: C, 77.56; H, 10.07.

Example 13 35,175 dipropionoxy 17u-ethynyl-5-andr0stene.--A suspension of 3.14 g. of 17a-ethynyl-5-androstene-3/3,17,8- diol in 15 ml. of pure propionic acid and 25 ml. of pure propionic anhydride at 25-32 C. was treated with 0.40

g. of powdered p-toluenesulfonic acid monohydrate. The

Analysis.--Ca1cd. for 0 11 0,: 0, 76.02; H, 8.92. Found: C, 76.30; H, 8.75.

Example 14 Example 1 3,3 isovaleroxy-I7fi-hydr0xy-17a-ethynyl-5-androstene was prepared from 17a-ethynyl-5-androstene-3,B,17,8-dio1 and isovaleric acid according to the method described in Example 9. The 3 3 isovaleroxy-17B-hydroxy-l7a-ethynyl-5-androstene thus obtained had the M. P. 119.4--

127.8 C. (corr.); [al =96.9:0.4 (1% in chloroform).

Analysis.Calcd. for C H O C, 78.35; H, 9.61. Found: C, 78.52; H, 9.84.

Example 16 3B isocaproxy-I 7,8-hydroxy-1 7a-ethynyl-5-andr0stene was prepared from 17a-ethynyl-5-androstene-3,6,17fi-dio1 and isocaproic acid according to the method described in Example 9. The 3/3-isocaproxy-17B-hydroxy-17a-ethyny1- S-androstene thus obtained had the M. P. 135.6138.4

C. (corr.); [u] =92.7:0.4 (1% in chloroform). Analysis.Calcd. for C H O C, 78.59; H, 9.77.

Found: C, 78.41; H, 9.49.

Example 17 Example 18 35 (CL-Ethyl n-butyroxy)-17,8-hydr0xy-17ot-etlzynylandrostane was prepared from 17a-ethynylandrostane-3fi, 17B-diol and Z-ethylbutyric acid according to the method described in Example 9. The 3/8-(a-ethyl-n-butyroxy'y l7j8-hydroxy-17a-ethynylandrostane thus obtained had the M. P. 141-143 C. (uncorr.).

Analysis.-Calcd. for C H O C, 78.21; H, 10.21. Found: C, 78.26; H, 9.84.

Example 19 3fl-heptan0yloxy-1 7B-hydroxy-17a-ethynyl-5-andr0stene was prepared from 17otethynyl-5-androstene-3fl,17,8-diol and heptanoic anhydride according to the method described in Example 1. -The 3fi-heptanoyloxy-17 3-hydroxy-17m-cthynyl-5-androstene thus obtained had the M. P. 89.097.2 C. (corn).

Analysis.-Calcd. for C H O C, 78.82; H, 9.92. Found: C, 78.60; H, 9.69. 1

Example 20 3B- nonanoyloxy- 17fihydroxy- 17aethynylandrostane was prepared from 17a ethynylandrostane-3;8,l7fi-diol and nonanoic acid according to the method described in Example 9. The 3fl-nonanoyloxy-17,8-hydoxy-17a-ethynylandrostane thus obtained had the M. P. 88-90" C. 1

(uncorr.).

Analysis.Calcd. for C H O C, 78.89; H, 10.59. Found: C, 78.77; H, 10.47.

7 Example. 21

3/3- decanoylaxy- 17 8 hydr gary- 17ozethynylandrastane was prepared from 17a-ethynylandrostane-3B,l7fl-diol and'dec'anoic acid accordi tb -theniethod described in Example The'BB-de'c ovlbiry 17B-hvdr0Xv-17oc ethynylandrostane thus obtained-had theM. P. 69-71 C. (uncorn).

Anizlysis.-Calc d. fo m- 33 C, 79510;"H,"10.7l. Found: C, 79.04; H, 10.78:

EXZznipZe'ZZ 3/3-heptan0yloxy- 17fihydroxy- 17aethynylandrostane was prepared from l7bi ethyriylandrostane-3B,17B-diol and heptanoic anhydride according to the method described in-Example The '3/3' heptanoyloXy-17 8-hydroxy-l7a-ethynylandro'stane thus obtained melted at 89.8-91.4" C. (corn).-

AnZzlysis.Ca1cd. for spa- 0 c, 78.45;'-H, 10.35. Found: C,78.54;H,'10121. I 7

Example 23' 3/3-(ecethyl-n-butyroxy)- 17,8 hy'klf'axy l 76iflzynyl= androstene was prepared from 17u-ethynyl-5-androstene- 3,3,17,8-diol and 2-eth'ylbutvric acid according to the method described in Example 9. I There was thus obtained 3 18- m-ethyl-n-butyroxy) -17 B-hydroxy- 17a-ethyny1- S-androstene, M. P. 17l'.4-l73 8 C. (corr.).

Analysis -Calcd. for (1 1-1 0 C, 78.59; H, 9.77. Found: C, 78.58; H, 10.07.

Example 24 3fi-nonan0y loxy-l 7fi-h ydr 0 xy-1 7vcethynyl-5-androstene was prepared from 17a-ethynyl-5-androstene and nonanoic acid according tothe method described in Example 9. The 3,3-nonanoyloxy-1713-hydroxy-17o -ethynyl-5-androstene thus obtained had the' M. P. 91.6934 0. (corn).

Analysis.--Ca1cd. fot C30H4603I C, H, Found: C, 79.24; H, 10.37.

Example 25 36-(7- carboxybutyroxy -1 7 8- hydrovcy-Z 70 ethynj'lah- 'drostane can be prepared from l7-ethynylandrostane- 3;8,17,8-di0l and glutaric anhydride according to the method described in Example 8.

2. A 35'- acyloXy-17 3- hydroxy-17d ethynylandrostane wherein the acyl group is" an. v:alkanoyl radical having from 3 to about 10 carbon atoms; 3. A 3 3- acyloXy-17fih'ydr'oxy-17heethynyl-5 androstene wherein the acyl group is.au.'alkano'yl radical having from 3 to about 10 carbon atoms.

4. A 3B-acyloxy-17flhyd'r'oxy-17aethynylandrostane wherein the acyl group isra carboxy-alkanoyl radical having 4 to 6 carbon atoms. I

5; A 3B-acyloxy-l7,8-hydroxy-17a-ethynyl-5-androstene wherein the acyl group is acarboXy-alkanoyl radical having 4 to 6 carbon atoms.

6. 3,8- propionoxy-Uflhydroxy- 17:- thynyl-S- androstene;

7. 3B-trimethylacetoxy-17B-hydroxy-17a-ethynylandrostane.

8. 3,8-caproxy-17fl-hydroxy-17a=ethynylandrostane 9. 3fi-succinoxy-17B-hydroxy-17a-ethynyl-S-androstene.

10. 35 butyroxy- 17(3- hydroxy- 17w ethynyl-S- androstene.

11. The process of preparing a 3B-acyloxy-17fi-hydroxy-17ck ethynylandrostane which comprises reacting 17a-ethynylandrostane-3B,l7B-diol with an alkanoic anhydride, (RCO) O, wherein RC0 is an alkyanoyl group having from 3 to about 10 carbon atoms.

12. The process of preparing a 3fi=acy1oxy-17B=hydroxy-l7a-ethynyl-5-androstene which comprises reacting 17wethynyl-5-androstene-35,17/8-diol with an alkanoic anhydride, (RCO) O, wherein RC0 is an alkanoyl group having from 3 to about 10 carbon atoms.

13.'The process of preparing a 3,8-acyloxy-l7fi-hydroxy-17a-ethynylandrostane which comprises reacting l7a-ethynylandrostane-3fi,17/8-di01 with an anhydride of an alkanedioic acid having from 4 to 6 carbon atoms.

14. The process of preparing a 3(3-acy1oxy-l7/3-hydr'oxy17ot-ethynyl-5-an-drostene Which comprises reacting 17a-ethynyl-5-androstene-3B,175-di0l with an anhydride of analkanedioicacid having from 4 to '6 carbon atoms.

15. The process of preparing a 3,6-acyloxy-17/3-hydroxy-17a-ethynylandrostane which comprises reacting 17a ethynylandrostane 3[3,l7fi-diol with an alkan'oic acid halide having from 3 to about 10 carbon atoms.

16. The process of preparing a 3 3acyloXy-l7[3-hy droxy-17nc ethynyl-5androstene which. comprises reacting 17a-ethynyl-S androstene-SB,17,8-diol with an alkanoic acid halide having from 3 to about 10 carbon atoms.

17. The process of preparing a compound selected from the group consisting of 3fi-acyloXy-17B-hydroxy- 17a'-ethyny1androstanes and 3B-acyloxy-l7l3-hydroxy-l7ae'thYnyl-S-androstenes which comprises reacting cethynylandrostane-3fi,17,6-diol or l7a-ethynyl-5-androstene-3/3,l7B-diol with an alkanoic acylating agent derived from an alkanoic acid having from 3 to about 10 carbon atoms in the case wherein the acyl group is an alkanoyl radical, and with an alkanedioic acylating agent derived from an alkanedioic acid having from 4 to 6 carbon atoms in the case wherein the acyl group is a carboxy-alkanoyl radical.

References Cited in the file of this patent Denmark Feb. 7, 1955 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,868,811 January 13, 1959 Raymond 0. Clinton et a1. It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 18, for estrongenicity read -estro enicity; column 3, line 4:, for carboxyl-acyl read carboxy-acy1-; line 54, for 775 read 77.95; line 59, for prepared 6.32 g. read -prepared from 6.32 g.; column 4, line 6, for portions, or read portions of; line 23 for weight read weighed-; column 6, line 5, for 3/3-z'80but1'0'wyread 3B-1Ls0Zutg r0wyline 71, for -hydoxyread hydroxy- Signed and sealed this 28th day of April 1959.

Attest: T. B. MORROW, ROBERT C. WATSON, Attuting Ofiacr. Uom/miuioner of Patents. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3B-ACYLOXY-17B-HYDROXY-17A-ETHYNYLANDROSTANES AND 3BACYLOXY-17B-HYDROXY-17A-ETHYNYL-5-ANDROSTENS WHEREIN THE ACYL GROUP IS A MEMBER OF THE GROUP CONSISTING OF ALKANOYL RADICALS HAVING FROM 3 TO ABOUT 10 CARBON ATOMS AND CARBOXY-ALKANOYL RADICALS HAVING FROM 4 TO 6 CARBON ATOMS. 